Surfactant protein A activation of atypical protein kinase C zeta in IkappaB-alpha-dependent anti-inflammatory immune regulation
Moulakakis, C.; Adam, S.; Seitzer, U.; Schromm, A.B.; Leitges, M.; Stamme, C.
Journal of Immunology 179(7): 4480-4491
2007
ISSN/ISBN: 0022-1767 PMID: 17878344 Document Number: 607052
The pulmonary collectin surfactant protein (SP)-A has a pivotal role in anti-inflammatory modulation of lung immunity. The mechanisms underlying SP-A-mediated inhibition of LPS-induced NF-kappa B activation in vivo and in vitro are only partially understood. We previously demonstrated that SP-A stabilizes I kappa B-alpha, the primary regulator of NF-kappa B, in alveolar macrophages (AM) both constitutively and in the presence of LPS. In this study, we show that in AM and PBMC from I kappa B-alpha knockout/I kappa B-beta knockin mice, SP-A fails to inhibit LPS-induced TNF-alpha production and p65 nuclear translocation, confirming a critical role for I kappa B-alpha in SP-A-mediated LPS inhibition. We identify atypical (a) protein kinase C (PKC) as a pivotal upstream regulator of SP-A-mediated I kappa B-alpha/NF-kappa B pathway modulation deduced from blocking experiments and confirmed by using AM from PKC zeta(-/-) mice. SP-A transiently triggers aPKCThr(410/403) phosphorylation, aPKC kinase activity, and translocation in primary rat AM. Coimmunoprecipitation experiments reveal that SP-A induces aPKC/p65 binding under constitutive conditions. Together the data indicate that anti-inflammatory macrophage activation via I kappa B-alpha by SP-A critically depends on PKC zeta activity, and thus attribute a novel, stimulus-specific signaling function to PKC in SP-A-modulated pulmonary immune response.